The present invention relates to a series of new urea and other amide derivatives which have valuable inhibitory activity against acyl-CoA: cholesterol acyl transferase (hereinafter referred to, as is conventional, as "ACAT"). The compounds are thus useful for the treatment and prophylaxis of arteriosclerosis, including atherosclerosis. The invention also provides methods and compositions using these new compounds for such treatment and prophylaxis as well as processes for their preparation.
Among the causes of ischemic cardiac insufficiency (which may result in angina, myocardial infarction and the like), arteriosclerosis, including atherosclerosis, is thought to be most important. These diseases are of considerable importance in the world today and can be fatal or can severely impair the quality of life of the sufferer. It is believed that the foam cells under the endothelial cell layer of blood vessels accumulate cholesterol esters, and that this is a major cause of arteriosclerosis.
Inhibitors of acyl-CoA: cholesterol acyl transferase inhibit the synthesis of cholesterol esters in the foam cells, diminish the accumulation of cholesterol esters in the foam cells and inhibit the formation and development of atheromatous morbidity due to the accumulation of cholesterol esters.
Additionally, it has been established that there is a correlation between arteriosclerosis and hypercholesterolemia. Cholesterols in food are absorbed as free cholesterol in the intestinal mucosal cell tract. They are then esterified by ACAT, and the resulting cholesterol ester can be passed into the blood. Therefore, an ACAT inhibitor inhibits any rise in the cholesterol concentration in the blood by inhibiting the absorption of food cholesterol into the blood.
For these reasons compounds having ACAT inhibiting activity are useful as therapeutic and/or prophylactic agents against arteriosclerosis.
Phenylpropionic acid amides and phenethylurea derivatives having ACAT inhibiting activity are well-known and are disclosed, for example, in European Patent Publications No. 591 830, 344 425, 415 123, 439 059 and 432 442 and WO 93/24 458. We believe European Patent Publication No. 591 830 to be the closest prior art to the present invention. The compounds of this prior art, however, differ from those of the present invention in the nature of the group hereinafter defined as R.sup.4.
We have now surprisingly discovered a series of new urea and other amide derivatives which have more potent inhibitory activity against ACAT and have better oral absorption than do the prior art compounds referred to above.